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Publications

Journal Article Epublish

PubMed: 40374812 DOI: 10.1007/s00262-025-04060-w

Actionable heterogeneity of hepatocellular carcinoma therapy-induced senescence.

Cancer Immunol Immunother 74(7):207

Authors: Pujan Engels, Andras Szolek, Sebastian Hörner, Georgios Vavouras Syrigos, Kim Hebbel, Michelle Schmidtke, Min Zhou, Maria Mateo-Tortola, Caroline Schönfeld, Sylwia Anna Stefanczyk, Katharina Wolter, Sepideh Babaei, Michael Schindler, Manfred Claassen, Daniel Dauch, Lars Zender, Ana Tapía-Abellán, Alexander N R Weber

Affiliations

  • Department of Innate Immunity, Institute of Immunology, University of Tübingen, Tübingen, Germany. iFIT Cluster of Excellence 2180, 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  • Department of Innate Immunity, Institute of Immunology, University of Tübingen, Tübingen, Germany.
  • Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
  • Department of Medical Virology, Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany. DZIF Partner Site Tübingen, Tübingen, Germany.
  • iFIT Cluster of Excellence 2180, 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  • Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  • German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany.
  • Department of Computer Science, University of Tübingen, Tübingen, Germany.
  • M3 Research Center, University Hospital Tübingen, Tübingen, Germany.
  • Institute for Bioinformatics and Medical Informatics, University of Tübingen, Tübingen, Germany.
  • Department of Medical Virology, Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany.
  • DZIF Partner Site Tübingen, Tübingen, Germany.
  • Department of Innate Immunity, Institute of Immunology, University of Tübingen, Tübingen, Germany.
  • iFIT Cluster of Excellence 2180, 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  • German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Cluster of Excellence 2124 CMFI, Controlling Microbes to Fight Infection, University of Tübingen, Tübingen, Germany.

Abstract

Therapy-induced senescence (TIS) is a stable cell cycle arrest in cancerous cells favoring immune control upon immune cell recruitment and activation via a senescence-associated secretory phenotype (SASP). Numerous studies have investigated the therapeutic applicability of TIS in hepatocellular carcinoma (HCC), a frequent cancer with high morbidity and mortality. Despite these efforts, a comprehensive understanding of how TIS may expose vulnerabilities specifically for immunotherapies, a potent means of cancer therapy, in HCC remains incomplete. Therefore, we conducted systematic studies to carefully characterize actionable and shared SASP- or other senescence-associated molecular parameters of TIS. We systematically compared the TIS inducers, etoposide and alisertib with a novel TIS inducer, CX5461, for their effects on SASP, surfaceome and innate immune clearance of representative human HCC cell lines. Surprisingly, all three compounds induced both metastasis surface antigens but also immunotherapeutically tractable antigens like CD95 (Fas), CD276 (B7-H3) and CD340 (Her2). This was verified in four representative HCC cell lines and publicly available datasets of HCC. Interestingly, alisertib, etoposide and CX5461 rendered senescent HCC vulnerable to be targeted by either T-cell-engaging bispecific antibodies or CAR NK cells. Collectively, our study indicates that heterogenous, but selective features of HCC senescence may be exploited by different immunotherapeutic approaches.

MeSH

Cells, Carcinoma, Hepatocellular, Neoplasms, Immunotherapy, Cell Line, Therapeutics, Etoposide

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